Superacid Group in "Organic Synthesis" Team, Université de Poitiers, CNRS UMR 7285 IC2MP, Bât. B28, 4 rue Michel Brunet, TSA 51106, 86073 Poitiers Cedex 09, France.
NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
J Med Chem. 2024 Nov 14;67(21):19460-19474. doi: 10.1021/acs.jmedchem.4c01795. Epub 2024 Oct 24.
Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited. In this work, we report β-(di) fluoropropyl diamines as effective CA IV inhibitors, opening real perspectives for a new mode of selective inhibition of this isoform. Inhibition data reveal that the essential structure core to ensure a potent and selective inhibition of CA IV is the -propyldiamine. Molecular modeling studies were employed to understand the binding mode of the synthesized amines. Conformational searches within the active site space carried out in an implicit solvent (water) model were also conducted.
碳酸酐酶（CA）IV 是一种膜结合酶，参与许多重要的生理病理过程，如心肌兴奋-收缩偶联、中枢神经系统（CNS）细胞外缓冲以及中风后的炎症反应调节。自 20 世纪 80 年代中期被发现以来，与其他同工酶相比，这种同工酶的研究还很不充分，这主要是因为目前缺乏针对该同工酶的选择性抑制剂。因此，人们迫切需要发现选择性 CA IV 抑制剂。在这项工作中，我们报道了β-（二）氟丙基二胺是有效的 CA IV 抑制剂，为这种同工酶的新型选择性抑制模式开辟了广阔的前景。抑制数据表明，确保对 CA IV 产生有效和选择性抑制的必需结构核心是 -丙基二胺。我们还进行了分子建模研究，以了解所合成胺的结合模式。在包含活性位点的空间内，我们还在隐式溶剂（水）模型中进行了构象搜索。
